Discovering small molecules that promote cardiomyocyte generation by modulating Wnt signaling

Terri T. Ni, Eric J. Rellinger, Amrita Mukherjee, Shuying Xie, Lauren Stephens, Curtis A. Thorne, Kwangho Kim, Jiangyong Hu, Ethan Lee, Larry Marnett, Antonis K. Hatzopoulos, Tao P. Zhong

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

We have developed a robust in vivo small-molecule screen that modulates heart size and cardiomyocyte generation in zebrafish. Three structurally related compounds (Cardionogen-1 to Cardionogen-3) identified from our screen enlarge the size of the developing heart via myocardial hyperplasia. Increased cardiomyocyte number in Cardionogen-treated embryos is due to expansion of cardiac progenitor cells. In zebrafish embryos and murine embryonic stem (ES) cells, Cardionogen treatment promotes cardiogenesis during and after gastrulation, whereas it inhibits heart formation before gastrulation. Cardionogen-induced effects can be antagonized by increasing Wnt/β-catenin signaling activity. We demonstrate that Cardionogen inhibits Wnt/β-catenin-dependent transcription in murine ES cells and zebrafish embryos. Cardionogen can rescue Wnt8-induced cardiomyocyte deficiency and heart-specific phenotypes during development. These findings demonstrate that in vivo small-molecule screens targeting heart size can reveal compounds with cardiomyogenic effects and identify underlying target pathways.

Original languageEnglish
Pages (from-to)1658-1668
Number of pages11
JournalChemistry and Biology
Volume18
Issue number12
DOIs
StatePublished - Dec 23 2011

Bibliographical note

Funding Information:
We are indebted to John Guan for his invaluable assistance in fish care and Alex Waterson for his efforts in chemical synthesis. We thank Geoffrey Burns for cmlc2-EGFP and cmlc2-DsRed fish, Randall Moon for hsp-wnt8 fish, G.J. Robbins for providing Myh6 promoter plasmid, and P. ten Dijke for BRE 2 -Luc construct. We are grateful to Bruce Appel, Scott Baldwin, Wenbiao Chen, Josh Gamse, Daqing Jin, and members of our laboratories for comments on the manuscript and helpful discussions. This research is supported in part by grants NIH-NS064852 (T.P.Z.), HL083958 (A.K.H.), NIH-UL1RR024975 (VICTR), and Fudan University-EZH1322001 (T.P.Z.).

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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